Biology:Angiogenesis inhibitor

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An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical drugs or diet. While angiogenesis is a critical part of wound healing and other favorable processes, certain types of angiogenesis are associated with the growth of malignant tumors. Thus angiogenesis inhibitors have been closely studied for possible cancer treatment. Angiogenesis inhibitors were once thought to have potential as a "silver bullet" treatment applicable to many types of cancer, but the limitations of anti-angiogenic therapy have been shown in practice.[1] Currently, angiogenesis inhibitors are recognized for their improvement of cancer immunotherapy [2][3] by overcoming endothelial cell anergy. Angiogenesis inhibitors are also used to effectively treat macular degeneration in the eye, and other diseases that involve a proliferation of blood vessels.[4][5][6]

Mechanism of action

When a tumor stimulates the growth of new vessels, it is said to have undergone an 'angiogenic switch'. The principal stimulus for this angiogenic switch appears to be oxygen deprivation, although other stimuli such as inflammation, oncogenic mutations and mechanical stress may also play a role. The angiogenic switch leads to tumor expression of pro-angiogenic factors and increased tumor vascularization.[7] Specifically, tumor cells release various pro-angiogenic paracrine factors (including angiogenin, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and transforming growth factor-β (TGF-β). These stimulate endothelial cell proliferation, migration and invasion resulting in new vascular structures sprouting from nearby blood vessels.[8] Cell adhesion molecules, such as integrins, are critical to the attachment and migration of endothelial cells to the extracellular matrix.[7]

VEGF pathway inhibition

Inhibiting angiogenesis requires treatment with anti-angiogenic factors, or drugs which reduce the production of pro-angiogenic factors, prevent them binding to their receptors or block their actions. Inhibition of the VEGF pathway has become the focus of angiogenesis research, as approximately 60% of malignant tumors express high concentrations of VEGF. Strategies to inhibit the VEGF pathway include antibodies directed against VEGF or VEGFR, soluble VEGFR/VEGFR hybrids, and tyrosine kinase inhibitors.[7][9] The most widely used VEGF pathway inhibitor on the market today is Bevacizumab.[citation needed] Bevacizumab binds to VEGF and inhibits it from binding to VEGF receptors.[10]

Endogenous regulation

Angiogenesis is regulated by the activity of endogenous stimulators and inhibitors. Endogenous inhibitors, found in the body naturally, are involved in the day-to-day process of regulating blood vessel formation. Endogenous inhibitors are often derived from the extracellular matrix or basement membrane proteins and function by interfering with endothelial cell formation and migration, endothelial tube morphogenesis, and down-regulation of genes expressed in endothelial cells.

During tumor growth, the action of angiogenesis stimulators surpasses the control of angiogenesis inhibitors, allowing for unregulated or less regulated blood vessel growth and formation.[11] Endogenous inhibitors are attractive targets for cancer therapy because they are less toxic and less likely to lead to drug resistance than some exogenous inhibitors.[7][9] However, the therapeutic use of endogenous inhibitors has disadvantages. In animal studies, high doses of inhibitors were required to prevent tumor growth and the use of endogenous inhibitors would likely be long-term.[11]

Inhibitors Mechanism
soluble VEGFR-1 and NRP-1 decoy receptors[12] for VEGF-B and PIGF
Angiopoietin 2 antagonist of angiopoietin 1
TSP-1 and TSP-2 inhibit cell migration, cell proliferation, cell adhesion and survival of endothelial cells
angiostatin and related molecules inhibit cell proliferation and induce apoptosis of endothelial cells
endostatin inhibit cell migration, cell proliferation and survival of endothelial cells
vasostatin, calreticulin inhibit cell proliferation of endothelial cells
platelet factor-4 inhibits binding of bFGF and VEGF
TIMP and CDAI inhibit cell migration of endothelial cells
ADAMTS1 and ADAMTS8
IFN-α, -β and -γ, CXCL10, IL-4, -12 and -18 inhibit cell migration of endothelial cells, downregulate bFGF
prothrombin (kringle domain-2), antithrombin III fragment inhibit cell proliferation of endothelial cells
prolactin VEGF
VEGI affects cell proliferation of endothelial cells
SPARC inhibit binding and activity of VEGF
osteopontin inhibit integrin signalling
maspin inhibits proteases
canstatin (a fragment of COL4A2) inhibits endothelial cell migration, induces apoptosis[13]
proliferin-related protein mannose 6-phosphate binding lysosomal protein[14]

A recent method for the delivery of anti-angiogenesis factors to tumor regions in cancer patients uses genetically modified bacteria that are able to colonize solid tumors in vivo, such as Clostridium, Bifidobacteria and Salmonella by adding genes for anti-angiogenic factors such as endostatin or IP10 chemokine and removing any harmful virulence genes. A target can also be added to the outside of the bacteria so that they are sent to the correct organ in the body. The bacteria can then be injected into the patient and they will locate themselves to the tumor site, where they release a continual supply of the desired drugs in the vicinity of a growing cancer mass, preventing it from being able to gain access to oxygen and ultimately starving the cancer cells.[15] This method has been shown to work both in vitro and in vivo in mice models, with very promising results.[16] It is expected that this method will become commonplace for treatment of various cancer types in humans in the future.[citation needed]

Exogenous regulation

Diet

Some common components of human diets also act as mild angiogenesis inhibitors and have therefore been proposed for angioprevention, the prevention of metastasis through the inhibition of angiogenesis. In particular, the following foods contain significant inhibitors and have been suggested as part of a healthy diet for this and other benefits:

Drugs

Research and development in this field has been driven largely by the desire to find better cancer treatments. Tumors cannot grow larger than 2mm without angiogenesis. By stopping the growth of blood vessels, scientists hope to cut the means by which tumors can nourish themselves and thus metastasize.

In addition to their use as anti-cancer drugs, angiogenesis inhibitors are being investigated for their use as anti-obesity agents, as blood vessels in adipose tissue never fully mature, and are thus destroyed by angiogenesis inhibitors.[32] Angiogenesis inhibitors are also used as treatment for the wet form of macular degeneration. By blocking VEGF, inhibitors can cause regression of the abnormal blood vessels in the retina and improve vision when injected directly into the vitreous humor of the eye.[33]

Overview

Inhibitors Mechanism
bevacizumab (Avastin) VEGF
itraconazole inhibits VEGFR phosphorylation, glycosylation, mTOR signaling, endothelial cell proliferation, cell migration, lumen formation, and tumor associated angiogenesis.[34][35][36]
carboxyamidotriazole Methionine aminopeptidase 2 inhibitors,[37] inhibit cell proliferation and cell migration of endothelial cells
TNP-470 (an analog of fumagillin)
CM101 activate immune system
IFN-α downregulate angiogenesis stimulators and inhibit cell migration of endothelial cells
IL-12 stimulate angiogenesis inhibitor formation
platelet factor-4 inhibits binding of angiogenesis stimulators
suramin
SU5416
thrombospondin
VEGFR antagonists
angiostatic steroids + heparin inhibit basement membrane degradation
Cartilage-Derived Angiogenesis Inhibitory Factor
matrix metalloproteinase inhibitors
angiostatin inhibit cell proliferation and induce apoptosis of endothelial cells
endostatin inhibit cell migration, cell proliferation and survival of endothelial cells
2-methoxyestradiol inhibit cell proliferation and cell migration and induce apoptosis of endothelial cells
tecogalan inhibit cell proliferation of endothelial cells
tetrathiomolybdate copper chelation which inhibits blood vessel growth
thalidomide inhibit cell proliferation of endothelial cells
thrombospondin inhibit cell migration, cell proliferation, cell adhesion and survival of endothelial cells
prolactin VEGF
αVβ3 inhibitors induce apoptosis of endothelial cells
linomide inhibit cell migration of endothelial cells
ramucirumab inhibition of VEGFR2[38]
tasquinimod Unknown[39]
ranibizumab VEGF[40]
sorafenib (Nexavar) inhibit kinases
sunitinib (Sutent)
pazopanib (Votrient)
everolimus (Afinitor)

File:Angiogenesis Inhibitors Image.tiff

Bevacizumab

Through binding to VEGFR and other VEGF receptors in endothelial cells, VEGF can trigger multiple cellular responses like promoting cell survival, preventing apoptosis, and remodeling cytoskeleton, all of which promote angiogenesis. Bevacizumab (brand name Avastin) traps VEGF in the blood, lowering the binding of VEGF to its receptors. This results in reduced activation of the angiogenesis pathway, thus inhibiting new blood vessel formation in tumors.[11]

After a series of clinical trials in 2004, Avastin was approved by the FDA, becoming the first commercially available anti-angiogenesis drug. FDA approval of Avastin for breast cancer treatment was later revoked on November 18, 2011.[41]

Thalidomide

Despite the therapeutic potential of anti-angiogenesis drugs, they can also be harmful when used inappropriately. Thalidomide is one such antiangiogenic agent. Thalidomide was given to pregnant women to treat nausea. However, when pregnant women take an antiangiogenic agent, the developing fetus will not form blood vessels properly, thereby preventing the proper development of fetal limbs and circulatory systems. In the late 1950s and early 1960s, thousands of children were born with deformities, most notably phocomelia, as a consequence of thalidomide use.[42]

Cannabinoids

According to a study published in the August 15, 2004 issue of the journal Cancer Research, cannabinoids, the active ingredients in marijuana, restrict the sprouting of blood vessels to gliomas (brain tumors) implanted under the skin of mice, by inhibiting the expression of genes needed for the production of vascular endothelial growth factor (VEGF).[43]

General side effects of drugs

Bleeding

Bleeding is one of the most difficult side effects to manage; this complication is somewhat inherent to the effectiveness of the drug. Bevacizumab has been shown to be the drug most likely to cause bleeding complications. [citation needed] While the mechanisms of bleeding induced by anti-VEGF agents are complicated and not yet totally understood, the most accepted hypothesis is that VEGF could promote endothelial cell survival and integrity in the adult vasculature and its inhibition may decrease capacity for renewal of damaged endothelial cells.[44]

Increased blood pressure

In a study done by ML Maitland, a mean blood pressure increase of 8.2 mm Hg systolic and 6.5 mm Hg diastolic was reported in the first 24 hours after the first treatment with sorafenib, a VEGF pathway inhibitor.[45][non-primary source needed]

Less common side effects

Because these drugs act on parts of the blood and blood vessels, they tend to have side effects that affect these processes. Aside from problems with hemorrhage and hypertension, less common side effects of these drugs include dry, itchy skin, hand-foot syndrome (tender, thickened areas on the skin, sometimes with blisters on palms and soles), diarrhea, fatigue, and low blood counts. Angiogenesis inhibitors can also interfere with wound healing and cause cuts to re-open or bleed. Rarely, perforations (holes) in the intestines can occur.[44]

See also

References

  1. ↑ "Cutting off cancer's supply lines". Nature 458 (7239): 686–7. April 2009. doi:10.1038/458686b. PMID 19360048. 
  2. ↑ Fukumura, D., et al., Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol, 2018. 15(5): p. 325-340. doi: 10.1038/nrclinonc.2018.29
  3. ↑ Huinen, Z., et al., Anti-angiogenic agents - overcoming tumor endothelial cell anergy and improving immunotherapy outcomes. Nat. Rev. Clin. Oncol., 2021. 18(8): p. 527-540. doi: 10.1038/s41571-021-00496-y
  4. ↑ Dudley, A.C. & Griffioen, A.W., Pathological angiogenesis: mechanisms and therapeutic strategies. Angiogenesis, 2023. doi: 10.1007/s10456-023-09876-7
  5. ↑ Cancer.com [homepage on the Internet]. National Cancer Institute at the National Institutes of Health; 2011 [cited 18 March 2014]. Available from: "Angiogenesis Inhibitors". http://www.cancer.gov/cancertopics/factsheet/Therapy/angiogenesis-inhibitors. 
  6. ↑ "Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration". Canadian Journal of Ophthalmology 40 (3): 352–68. June 2005. doi:10.1016/S0008-4182(05)80078-X. PMID 15947805. 
  7. ↑ 7.0 7.1 7.2 7.3 "Endogenous angiogenesis inhibitors". APMIS 112 (7–8): 496–507. 2004. doi:10.1111/j.1600-0463.2004.apm11207-0809.x. PMID 15563312. 
  8. ↑ Milosevic, Vladan; Edelmann, Reidunn J.; Fosse, Johanna Hol; Östman, Arne; Akslen, Lars A. (2022), Akslen, Lars A.; Watnick, Randolph S., eds., "Molecular Phenotypes of Endothelial Cells in Malignant Tumors" (in en), Biomarkers of the Tumor Microenvironment (Cham: Springer International Publishing): pp. 31–52, doi:10.1007/978-3-030-98950-7_3, ISBN 978-3-030-98950-7, https://doi.org/10.1007/978-3-030-98950-7_3, retrieved 2022-07-13 
  9. ↑ 9.0 9.1 "Endogenous angiogenesis inhibitors and their therapeutic implications". The International Journal of Biochemistry & Cell Biology 33 (4): 357–69. April 2001. doi:10.1016/s1357-2725(01)00023-1. PMID 11312106. 
  10. ↑ "Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions". Clinical Cancer Research 13 (4): 1098–106. February 2007. doi:10.1158/1078-0432.CCR-06-1989. PMID 17317817. 
  11. ↑ 11.0 11.1 11.2 "Endogenous inhibitors of angiogenesis". Cancer Research 65 (10): 3967–79. May 2005. doi:10.1158/0008-5472.CAN-04-2427. PMID 15899784. 
  12. ↑ Hugo H. Marti, "Vascular Endothelial Growth Factor", Madame Curie Bioscience Database (Landes Bioscience), https://www.ncbi.nlm.nih.gov/books/NBK6149/, retrieved January 25, 2012 
  13. ↑ "Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth". The Journal of Biological Chemistry 275 (2): 1209–15. January 2000. doi:10.1074/jbc.275.2.1209. PMID 10625665. 
  14. ↑ "Proliferin secreted by cultured cells binds to mannose 6-phosphate receptors". The Journal of Biological Chemistry 263 (7): 3521–7. March 1988. doi:10.1016/S0021-9258(18)69101-X. PMID 2963825. 
  15. ↑ Gardlik, R., Behuliak, M., Palffy, R., Celec, P., & Li, C. J. (2011). Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy. Gene therapy, 18(5), 425-431.
  16. ↑ Xu, Y. F., Zhu, L. P., Hu, B., Fu, G. F., Zhang, H. Y., Wang, J. J., & Xu, G. X. (2007). A new expression plasmid in Bifidobacterium longum as a delivery system of endostatin for cancer gene therapy. Cancer gene therapy, 14(2), 151-157.
  17. ↑ "Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer". Oncology Reports 16 (4): 885–91. October 2006. doi:10.3892/or.16.4.885. PMID 16969510. http://www.spandidos-publications.com/or/article.jsp?article_id=or_16_4_885. 
  18. ↑ "Isolation of an anti-angiogenic substance from Agaricus blazei Murill: its antitumor and antimetastatic actions". Cancer Science 95 (9): 758–64. September 2004. doi:10.1111/j.1349-7006.2004.tb03258.x. PMID 15471563. 
  19. ↑ "Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action". The Journal of Nutrition 131 (5): 1409–13. May 2001. doi:10.1093/jn/131.5.1409. PMID 11340091. 
  20. ↑ Liu, Zhijun; Schwimer, Joshua; Liu, Dong; Greenway, Frank L.; Anthony, Catherine T.; Woltering, Eugene A. (2005). "Black Raspberry Extract and Fractions Contain Angiogenesis Inhibitors". Journal of Agricultural and Food Chemistry 53 (10): 3909–3915. doi:10.1021/jf048585u. PMID 15884816. 
  21. ↑ "Ganoderma lucidum suppresses angiogenesis through the inhibition of secretion of VEGF and TGF-beta1 from prostate cancer cells". Biochemical and Biophysical Research Communications 330 (1): 46–52. April 2005. doi:10.1016/j.bbrc.2005.02.116. PMID 15781230. 
  22. ↑ "Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy". Anticancer Research 22 (3): 1737–54. May 2002. PMID 12168863. 
  23. ↑ "Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curative resections of gastric cancer". Cancer Immunol Immunother 56 (6): 905–11. June 2007. doi:10.1007/s00262-006-0248-1. PMID 17106715. 
  24. ↑ "Antimetastatic effects of PSK (Krestin), a protein-bound polysaccharide obtained from basidiomycetes: an overview". Cancer Epidemiology, Biomarkers & Prevention 4 (3): 275–81. 1995. PMID 7606203. 
  25. ↑ "Grifola frondosa (maitake mushroom) water extract inhibits vascular endothelial growth factor-induced angiogenesis through inhibition of reactive oxygen species and extracellular signal-regulated kinase phosphorylation". Journal of Medicinal Food 11 (4): 643–51. December 2008. doi:10.1089/jmf.2007.0629. PMID 19053855. 
  26. ↑ "Phellinus linteus suppresses growth, angiogenesis and invasive behaviour of breast cancer cells through the inhibition of AKT signalling". British Journal of Cancer 98 (8): 1348–56. April 2008. doi:10.1038/sj.bjc.6604319. PMID 18362935. 
  27. ↑ "Protein glycation inhibitors from the fruiting body of Phellinus linteus". Biological & Pharmaceutical Bulletin 31 (10): 1968–72. October 2008. doi:10.1248/bpb.31.1968. PMID 18827365. 
  28. ↑ "Green tea catechin, epigallocatechin-3-gallate, inhibits vascular endothelial growth factor angiogenic signaling by disrupting the formation of a receptor complex". International Journal of Cancer 118 (7): 1635–44. April 2006. doi:10.1002/ijc.21545. PMID 16217757. 
  29. ↑ 29.0 29.1 Smith, Roderick. Antiangiogenic Substances in Blackberries, Licorice May Aid Cancer Prevention. The Angiogenesis Foundation. 6 May 2009.[unreliable medical source?]
  30. ↑ "Antiangiogenic phytochemicals and medicinal herbs". Phytotherapy Research 25 (1): 1–10. January 2011. doi:10.1002/ptr.3224. PMID 20564543. 
  31. ↑ "10-Hydroxy-2-decenoic acid, a major fatty acid from royal jelly, inhibits VEGF-induced angiogenesis in human umbilical vein endothelial cells". Evidence-Based Complementary and Alternative Medicine 6 (4): 489–94. December 2009. doi:10.1093/ecam/nem152. PMID 18955252. 
  32. ↑ "Targeting angiogenesis as treatment for obesity". Arteriosclerosis, Thrombosis, and Vascular Biology 32 (2): 161–2. February 2012. doi:10.1161/ATVBAHA.111.241992. PMID 22258895. 
  33. ↑ "Neovascular age-related macular degeneration: individualizing therapy in the era of anti-angiogenic treatments". Ophthalmology 120 (5 Suppl): S23–5. May 2013. doi:10.1016/j.ophtha.2013.01.059. PMID 23642783. 
  34. ↑ "Inhibition of angiogenesis by the antifungal drug itraconazole". ACS Chemical Biology 2 (4): 263–70. April 2007. doi:10.1021/cb600362d. PMID 17432820. 
  35. ↑ "Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer". Cancer Research 71 (21): 6764–72. November 2011. doi:10.1158/0008-5472.CAN-11-0691. PMID 21896639. 
  36. ↑ "Cholesterol trafficking is required for mTOR activation in endothelial cells". Proceedings of the National Academy of Sciences of the United States of America 107 (10): 4764–9. March 2010. doi:10.1073/pnas.0910872107. PMID 20176935. 
  37. ↑ Goya Grocin, Andrea; Kallemeijn, Wouter W.; Tate, Edward W. (October 2021). "Targeting methionine aminopeptidase 2 in cancer, obesity, and autoimmunity". Trends in Pharmacological Sciences 42 (10): 870–882. doi:10.1016/j.tips.2021.07.004. 
  38. ↑ Ramucirumab (Cyramza) package insert
  39. ↑ Ruch, Joshua M.; Hussain, Maha H. (15 May 2011). "Evolving Therapeutic Paradigms for Advanced Prostate Cancer" (in en). Oncology 25 (6): 496–504, 508. PMID 21717904. https://www.cancernetwork.com/view/evolving-therapeutic-paradigms-advanced-prostate-cancer. Retrieved 9 May 2022. 
  40. ↑ "Ranibizumab for neovascular age-related macular degeneration". The New England Journal of Medicine 355 (14): 1419–31. October 2006. doi:10.1056/NEJMoa054481. PMID 17021318. 
  41. ↑ FDA News Release on Avastin, https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm280536.htm, retrieved 2014-04-15 
  42. ↑ "Thalidomide: the tragedy of birth defects and the effective treatment of disease". Toxicological Sciences 122 (1): 1–6. July 2011. doi:10.1093/toxsci/kfr088. PMID 21507989. 
  43. ↑ "Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas". Cancer Research 64 (16): 5617–23. August 2004. doi:10.1158/0008-5472.CAN-03-3927. PMID 15313899. 
  44. ↑ 44.0 44.1 "Side effects of anti-angiogenic drugs". Thrombosis Research 129: S50–3. April 2012. doi:10.1016/S0049-3848(12)70016-6. PMID 22682133. 
  45. ↑ "Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment". Clinical Cancer Research 15 (19): 6250–7. October 2009. doi:10.1158/1078-0432.CCR-09-0058. PMID 19773379. 

Further reading

External links



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